System and method for detecting a possible loss of integrity of a flexible bag for biopharmaceutical product

Abstract

Integrity of a flexible bag is verified by a testing system, using helium to detect existence of a possible hole. The flexible bag is preliminary placed in vacuum chamber of a fluid-tightly isolated enclosure. After connecting a port of the bag to a helium feeding pipe, vacuum suction is performed to obtain vacuum outside the bag in the enclosure. Then, a first amount of helium is diffused in the internal volume of the enclosure through a gas permeable wall, to increase helium partial pressure outside the flexible bag. After, in a test phase while said vacuum suction is still performed, the bag is filled with a second amount of helium. A detector detects information representative of helium partial pressure in the internal volume, to allow detection of helium escaping from the bag, by analysis of a helium partial pressure drop.

The invention claimed is: 
     
       1. A testing system for verifying the integrity of a flexible bag, using a gas tracer, comprising:
 an enclosure delimiting a vacuum chamber in which an internal volume is fluid-tightly isolated from outside of the enclosure in an operating configuration of the enclosure; 
 first helium supplying device provided with a feeding pipe for filling the flexible bag at a filling step with helium, via an outlet of the feeding pipe when the flexible bag is placed in the vacuum chamber so as to be surrounded by the internal volume; 
 a vacuum suction assembly for performing vacuum suction and extracting gas from the internal volume outside the flexible bag, in a suction mode; 
 at least one pressure measurement member for detecting helium partial pressure in a detection area of the internal volume, the detection area communicating with a suction inlet of the vacuum suction assembly; 
 at least one source of pressurized helium intended to be introduced inside the flexible bag; wherein the testing system further comprises: 
 a second helium supplying device for adding helium in the internal volume the flexible bag, the second helium supplying device comprising a feeding member that is:
 distinct from the feeding pipe, 
 in fluid communication with a gas source; 
 
 a control unit for controlling the first helium supplying device and the second helium supplying device, and adapted to trigger the second helium supplying device before the first helium supplying device; and 
 an analysis module using to use information representative of helium partial pressure detected over time by the pressure measurement member before and after the filling step, the analysis module ( 15 ) being configured to detect a helium leak on the basis of said information. 
 
     
     
       2. The system according to  claim 1 , wherein the analysis module is adapted to use information representative of evolution over time of helium partial pressure detected by the pressure measurement member, after the filling step, in order to obtain a test result representative of a helium partial pressure drop in the detection area, the analysis module being configured to:
 use information representative of helium partial pressure detected by the pressure measurement member after an addition of helium by the second helium supplying device, for a period that includes a period subsequent to the filling step, when the vacuum suction assembly is in the suction mode; 
 subtract a determined background value from raw measurement, after determining the determined background value on the basis of information representative of helium partial pressure detected by the pressure measurement member before the filling step, when the vacuum suction assembly is in the suction mode; and 
 compare the test result to at least one reference result, so as to determine if the flexible bag filled with helium is considered to have or not to have passed the integrity verification. 
 
     
     
       3. The system according to  claim 2 , wherein the second helium supplying device comprises a valve, preferably a solenoid valve, upstream from the feeding member, the feeding member having a gas permeable wall to limit rate of helium added in the internal volume. 
     
     
       4. The system according to  claim 2 , wherein the control unit is configured to control:
 a first valve allowing circulation of helium in the feeding pipe in the filling step; and 
 a second valve allowing circulation of helium in the feeding member. 
 
     
     
       5. The system according to  claim 2 , wherein the at least one source of pressurized helium is a helium source including a single tank outside the internal volume for containing all helium to be injected in the vacuum chamber, the single tank being operatively coupled to the first helium supplying device and to the second helium supplying device. 
     
     
       6. The system according to  claim 1 , wherein the second helium supplying device comprises a valve, preferably a solenoid valve, upstream from the feeding member, the feeding member having a gas permeable wall to limit rate of helium added in the internal volume. 
     
     
       7. The system according to  claim 6 , wherein the second helium supplying device comprises an additional valve, preferably a solenoid valve, downstream from the feeding member. 
     
     
       8. The system according to  claim 6 , wherein the gas permeable wall comprises a microporous and/or mesoporous membrane of silicone rubber or glass. 
     
     
       9. The system according to  claim 1 , wherein the control unit is configured to control:
 a first valve allowing circulation of helium in the feeding pipe in the filling step; and 
 a second valve allowing circulation of helium in the feeding member. 
 
     
     
       10. The system according to  claim 1 , wherein the feeding member comprises a tube made of silicone or glass adapted to supply helium by diffusion through a silicone wall of the tube. 
     
     
       11. The system according to  claim 1 , wherein the at least one source of pressurized helium is a helium source including a single tank outside the internal volume for containing all helium to be injected in the vacuum chamber, the single tank being operatively coupled to the first helium supplying device and to the second helium supplying device. 
     
     
       12. The system according to  claim 1 , comprising:
 two plates that are in a spaced relationship, preferably parallel; 
 a housing for receiving the flexible bag between the two plates, the plates forming constraining plates for constraining expansion of the flexible bag when filled with helium during filling step. 
 
     
     
       13. A test method using a tracer gas for verifying integrity of a flexible bag in order to detect existence of a possible hole, the test method comprising:
 in a preparation phase:
 providing a testing system comprising an enclosure that delimits a vacuum chamber adapted to be fluid-tightly isolated from outside of the enclosure in an operating configuration of the enclosure; 
 providing an injection device suitable for delivery of a tracer gas in the vacuum chamber, the tracer gas being preferably helium; 
 placing the flexible bag in the vacuum chamber and connecting a port of the bag to a feeding pipe in communication with a source of a tracer gas; 
 performing vacuum suction, in order to obtain vacuum outside the flexible bag in an internal volume of the vacuum chamber-; 
 performing a gas tracer injection by supplying an amount of tracer gas, by the injection device, in the internal volume outside the flexible bag; and 
 
 in a test phase, while said vacuum suction is still performed:
 filling the flexible bag with an amount of the tracer gas at a filling step; 
 detecting information representative of the partial pressure of the tracer gas outside the flexible bag in the internal volume, to allow detection of this tracer gas escaping from the flexible bag, by using at least one pressure measurement member; 
 then, in a subsequent step, comparing a test result representative of a tracer gas partial pressure drop in the internal volume outside the flexible bag, which is obtained using the at least one pressure measurement member, to at least one reference result, so as to determine if the flexible bag is considered to have or not to have passed the integrity verification. 
 
 
     
     
       14. The test method according to  claim 13 , wherein in the test phase, comparison between the test result and the reference result is performed in a time slot comprised between  3  seconds and  10  seconds after starting the filling step. 
     
     
       15. The test method according to  claim 13 , wherein the tracer gas is helium, the test method further comprising in the preparation phase:
 performing vacuum suction inside the flexible bag to empty an internal space of the flexible bag; 
 measuring the partial pressure of helium in a detection area of the internal volume; 
 calculating a first time derivative of the partial pressure of helium in the detection area; 
 wherein, when partial pressure of helium measured in the detection area reaches a trigger point, it is checked if first time derivative of partial pressure of helium is in a predetermined range, between a lower limit and an upper limit, and only if the first time derivative of partial pressure of helium is outside the predetermined range, said injection is performed by the injection device. 
 
     
     
       16. The test method according to  claim 13 , wherein the gas tracer is helium and wherein, in the preparation phase, the amount of helium is supplied in the internal volume ( 10   a ) outside the flexible bag ( 2 ) after a helium partial pressure has been measured in the internal volume ( 10   a ) as low as or below a predetermined threshold. 
     
     
       17. The test method according to  claim 13 , wherein the gas tracer is helium and wherein the reference result is:
 either a predefined pressure at a given time after start of the filling step, or 
 or a predefined pressure drop threshold, obtained at a given time after start of the filling step by calculating a time derivative of a helium leak rate as detected by at least one pressure measurement member in a detection area of the internal volume. 
 
     
     
       18. The test method according to  claim 13 , wherein the filling step is performed in order to have the flexible bag maintained between two expansion-limiting plates spaced apart from and facing one another, suitable for not obstructing any leak in the wall of the flexible bag placed against them. 
     
     
       19. The test method according  claim 13 , wherein the flexible bag constitutes or is a part of a device under test intended to receive biopharmaceutical product and is provided with several flexible pipes each connected to a respective port of the device under test, the device under test being placed in the chamber before performing vacuum suction,
 and wherein, in the preparation phase, performing vacuum suction implies evacuating gas at different suction areas of the enclosure, in order to obtain vacuum inside the flexible bag and outside the flexible bag in the enclosure. 
 
     
     
       20. A testing system for verifying the integrity of a flexible bag, using a gas tracer, comprising:
 an enclosure delimiting a vacuum chamber in which an internal volume is fluid-tightly isolated from outside of the enclosure in an operating configuration of the enclosure; 
 a first gas supplying device provided with a feeding pipe for filling the flexible bag at a filling step with gas, via an outlet of the feeding pipe when the flexible bag is placed in the vacuum chamber so as to be surrounded by the internal volume; 
 a vacuum suction assembly for performing vacuum suction and extracting gas from the internal volume outside the flexible bag, in a suction mode; 
 at least one pressure measurement member for detecting gas partial pressure in a detection area of the internal volume, the detection area communicating with a suction inlet of the vacuum suction assembly; 
 at least one source of pressurized gas to be introduced inside the flexible bag; 
 wherein the testing system further comprises: 
 a second gas supplying device for adding gas in the internal volume outside the flexible bag, the second gas supplying device comprising a feeding member that is:
 distinct from the feeding pipe; 
 in fluid communication with a gas source; and 
 
 a control unit for controlling the first gas supplying device and the second gas supplying device, and adapted to trigger the second gas supplying device before the first gas supplying device; and 
 an analysis module to use information representative of evolution over time of gas partial pressure detected by the pressure measurement member before and after the filling step, the analysis module being configured to detect a gas leak on the basis of said information.